The broad objective of the current proposal was to develop methods for quantifying hepatic glucose production in human subjects, without the use of surgical intervention, or radioisotopes. In the second year of the current project, a sensitive method for measurement of total glucose production was developed using glucose-C13. The sensitivity, precision and accuracy are such that tracer quantities of the label may be employed. Secondly, a physiological model was developed which permitted the control of blood glucose at a projected level in human subjects, so that hormonal effects have been evaluated at a standardized glucose concentration. Third, the factors initiating hepatic glucose production in the newborn dog were evaluated; and the relationship between glycogenolysis and gluconeogenesis in the maintenance of hepatic glucose production were explored in the isolated perfused canine liver. The current proposal will apply the physiological models developed to pharmacological studies of hormonal effects on hepatic glucose production in the adult; and to the evalution of hepatic glucose production in neonatal hypoglycemia.